Selective inhibition of CTCF binding by iAs directs TET-mediated reprogramming of 5-hydroxymethylation patterns in iAs-transformed cells

Matthew Rea, Tyler Gripshover, Yvonne Fondufe-Mittendorf

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Methylation at cytosine (5mC) is a fundamental epigenetic DNA modification recently associated with iAs-mediated carcinogenesis. In contrast, the role of 5-hydroxymethylcytosine (5hmC), the oxidation product of 5mC in iAs-mediated carcinogenesis is unknown. Here we assess the hydroxymethylome in iAs-transformed cells, showing that dynamic modulation of hydroxymethylated DNA is associated with specific transcriptional networks. Moreover, this pathologic iAs-mediated carcinogenesis is characterized by a shift toward a higher hydroxymethylation pattern genome-wide. At specific promoters, hydroxymethylation correlated with increased gene expression. Furthermore, this increase in hydroxymethylation occurs concurrently with an upregulation of ten-eleven translocation (TET) enzymes that oxidize 5-methylcytosine (5mC) in DNA. To gain an understanding into how iAs might impact TET expression, we found that iAs inhibits the binding of CTCF at the proximal, weak CTCF binding sites of the TET1 and TET2 gene promoters and enhances CTCF binding at the stronger distal binding site. Further analyses suggest that this distal site acts as an enhancer, thus high CTCF occupancy at the enhancer region of TET1 and TET2 possibly drives their high expression in iAs-transformed cells. These results have major implications in understanding the impact of differential CTCF binding, genome architecture and its consequences in iAs-mediated pathogenesis.

Original languageEnglish
Pages (from-to)124-133
Number of pages10
JournalToxicology and Applied Pharmacology
Volume338
DOIs
StatePublished - Jan 1 2018

Bibliographical note

Funding Information:
We would like to thank the Markey Cancer Center's Research Communications Office for manuscript editing and assistance with graphic design (P30 CA177558). GEO accession numbers for Methyl-MiniSeq data is GSE85012 and RRHP data is GSE103626 this work was supported by NSF grant MCB 1517986 to YFN-M, NIEHS grant R01-ES024478 , TG was supported by NIEHS R25ES027864 to the SURES program at UK, and NIH T32 grant 165990 to MR, through Markey Cancer Center at University of Kentucky.

Publisher Copyright:
© 2017

Keywords

  • 5hmC
  • EMT
  • Epigenetics
  • Inorganic arsenic
  • RRHP
  • TET

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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